It is very important to repress inflammation in the therapy of respiratory inflammatory diseases such as asthma, chronic obstructive pulmonary disease (COPD) and the like.
Asthma is a chronic inflammatory disease of the airways resulting from the hyper-response of the immune system. In the late 1980s, it was discovered that proliferating helper T cells, which develop into effector T cells, differentiate into two major subtypes of cells known as Th1 and Th2 cells that act to activate cellular immune and humoral immune systems, respectively, and that Th1 and Th2 cells antagonize each other. Hence, asthma is now understood as a kind of inflammation which is predominantly driven by eosinophils that are elicited by Th2 cytokines stimulated by IgE in response to an allergen [Robinson D S, Hamid Q, Ying S, Tsicopoulos A, Barkans J, Bentley A M, Corrigan C, Durham S R, Kay A B. Predominant Th2-like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med 1992; 326:298-304]. The Th2 cytokine IL-13 was identified to induce all the features of allergic asthma in mouse models [Grunig G, Warnock M, Wakil A E, Venkayya R, Brombacher F, Rennick D M, Sheppard D, Mohrs M, Donaldson D D, Locksley R M, et al. Requirement for IL-13 independently of IL-4 in experimental asthma. Science 1998; 282: 2261-2263; Wills-Karp M, Luyimbazi J, Xu X, Schofield B, Neben T Y, Karp C L, Donaldson D D. Interleukin-13: central mediator of allergic asthma. Science 1998; 282:2258-2261].
However, non-eosinophilic asthma, which accounts for a significant number of the cases of asthma, cannot be explained by the Th2-driven mechanism [Douwes J, Gibson P, Pekkanen J, Pearce N. Non-eosinophilic asthma: importance and possible mechanisms. Thorax. 2002; 57:643-8; Fahy J V. Eosinophilic and neutrophilic inflammation in asthma: insights from clinical studies. Proc Am Thorac Soc. 2009; 6:256-9]. In non-eosinophilic or neutrophilic asthma, neutrophils are much more predominant than eosinophils as is implied by the name. Patients with non-eosinophilic asthma have been noted to have severer asthma or suffer a higher exacerbation although there is no increase in the eosinophil population in the airways compared to patients with eosinophilic asthma. A clinical study by inhalation of corticosteroids and placebos showed that non-eosinophilic asthma was distinctly different from eosinophilic asthma and showed little response to steroid treatment [Berry M, Morgan A, Shaw D E, Parker D, Green R, Brightling C, Bradding P, Wardlaw A J, Pavord I D. Pathological features and inhaled corticosteroid response of eosinophilic and non-eosinophilic asthma. Thorax. 2007; 62(12):1043-9].
Recently, Th17 cells were discovered as a new subset of T helper cells, which are considered developmentally distinct from Th1 and Th2 cells. CD4+ or CD8+ T cells are known to produce IL-17 [Langrish C L, Chen Y, Blumenschein W M, Mattson J, Basham B, Sedgwick J D, McClanahan T, Kastelein R A, Cua D J. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 2005; 201:233-240; Curtis M M, Way S S, Wilson C B. IL-23 promotes the production of IL-17 by antigen-specific CD8 T cells in the absence of IL-12 and type-I interferons. J Immunol 2009; 1:381-7; Ciric B, El-behi M, Cabrera R, Zhang G X, Rostami A. IL-23 drives pathogenic IL-17-producing CD8+ T cells. J Immunol 2009; 182:5296-305]. Although there is an expectation that Th17 cells might be associated with eosinophilic inflammation, the implication of Th17 cells or their cytokine IL-17 in asthma has not been revealed [Mo, Ji Hoon. T cell differentiation and Th17. Korean Journal of Otorhinolaryngology—Head and Neck Surgery 2008; 51:688-93]. More interestingly, continued Th17-mediated inflammatory response has recently been reported to induce the onset of colon cancer in the mucosal membrane [Wu et al. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat Med. 5(9):1016-22 (2009)].
In the meanwhile, overexpressed vascular endothelial growth factor (VEGF) causes airway remodeling and Th2 cells, together with endothelial cells, secrete VEGF upon allergic inflammation [Lee C G, Link H, Baluk P, Homer R J, Chapoval S, Bhandari V, Kang M J, Cohn L, Kim Y K, McDonald D M, Elias J A. Vascular endothelial growth factor (VEGF) induces remodeling and enhances TH2-mediated sensitization and inflammation in the lung. Nat Med 2004; 10:1095-1103]. Nowhere has the correlation between Th17 cells and VEGF or VEGFR (vascular endothelial growth factor receptor) been revealed prior to the present invention.
Among the main subtypes of VEGFRs are VEGFR-1, VEGFR-2 and VEGFR-3, which are also designated Flt-1, KDR or Flk-1, and Flt-4, respectively.